Little by little, the molecular underpinnings of facioscapulohumeral muscular dystrophy (FSHD) are yielding to scientific investigations. The latest revelations about a protein known as DUX4, announced in October, could bring a treatment for FSHD closer to the clinic.

About recent FSHD research

In August 2010, an MDA-supported multinational team announced that two genetic changes on chromosome 4 — a contracted region of DNA in a region called D4Z4 and a "permissive" signal nearby that "opens" part of the DNA in D4Z4 — were needed to cause the disease. (See Not One But Two DNA Changes Are Needed to Cause FSHD.) At that time, the scientists announced that FSHD-affected muscle cells were reading the DNA for a gene called DUX4 as "open," whereas cells normally read this DNA as "closed." When the DUX4 DNA is read as open, it's transcribed by cells into RNA and then, with the help of the permissive ("polyadenylation") signal, into DUX4 protein, with apparently damaging consequences to muscle tissue.

Now, an MDA-supported team that comprises many of the same researchers has added to the August findings by supplying more information about the enigmatic DUX4 gene and protein.

They've found that full-length DUX4 protein is normally active only during early development and that the gene for DUX4 is normally "silenced" via closed DNA after that point. However, in the muscles and possibly in other tissues of people with FSHD, the DUX4 gene is mistakenly activated because of changes on chromosome 4, allowing some of this developmental protein to be produced.

The scientists say that FSHD represents the first human disease to be associated with the incomplete silencing of a gene that's normally expressed only during early development.

About the new findings

Stephen Tapscott at the Fred Hutchinson Cancer Research Institute in Seattle coordinated the research team, which received MDA support and published its findings online Oct. 28, 2010, in PLoS Genetics.

The findings confirm and extend prior FSHD studies by analyzing a large number of laboratory-cultured muscle cells from people with and without FSHD; studying RNA (the chemical step between DNA and protein synthesis) from muscle biopsy samples taken from people with and without FSHD; identifying a shortened form of DUX4 RNA in the muscle cells of people without FSHD and a full-length form of DUX4 RNA and full-length DUX4 protein in the muscle cells of people with FSHD; finding relatively high amounts of full-length DUX4 RNA in human testes and stem cells.

The investigators say their data provide a basis for explaining the molecular underpinnings of FSHD in the following way:

Normally, full-length DUX4 RNA is made from the D4Z4 region on chromosome 4 in stem or stemlike cells.

Normally, in mature ("differentiated") cells, DUX4 RNA expression from the D4Z4 region is, for the most part, repressed (silenced). Some DUX4 DNA escapes repression, allowing DUX4 RNA to be made, but in a shortened form, giving rise to a shortened DUX4 protein.

In FSHD-affected cells, a contracted D4Z4 DNA region on chromosome 4 interferes with DUX4 gene silencing and also allows full-length, rather than short-form, DUX4 to be made when silencing is lifted.

Full-length DUX4, when produced after early development and in cells that are not stem cells, can cause damaging cellular changes. Short-form DUX4 protein does not appear to cause these changes.

MDA's role

MDA supported study team members Galina Filippova and Daniel Miller at the University of Washington-Seattle and Silvere van der Maarel at Leiden University Medical Center in the Netherlands. Rabi Tawil, who co-directs the MDA clinic at the University of Rochester (N.Y.) Medical Center, was also part of this team. Miller, Tapscott, Tawil and van der Maarel also were authors on the paper announcing the August 2010 findings about FSHD.

Meaning for people with FSHD

The new findings "validate DUX4 as a target for future FSHD therapies," Tapscott said.

It's possible that strategies to block DUX4 either at the genetic level or the protein level could be developed and that these strategies would be beneficial to people with FSHD.

However, targeting such therapies precisely to the cells where DUX4 is being produced and precisely to DUX4 DNA, RNA or protein will no doubt pose many challenges.